US6639068B1 - Method of preparing highly pure cefpodoxime proxetil - Google Patents

Method of preparing highly pure cefpodoxime proxetil Download PDF

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US6639068B1
US6639068B1 US10/111,557 US11155702A US6639068B1 US 6639068 B1 US6639068 B1 US 6639068B1 US 11155702 A US11155702 A US 11155702A US 6639068 B1 US6639068 B1 US 6639068B1
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cefpodoxime
salt
added
mixture
isomer
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Gwan-Sun Lee
Young-Kil Chang
Jae-Heon Lee
Chul-Hyun Park
Gha-Seung Park
Keum-Shin Jung
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Hanmi Pharmaceutical Co Ltd
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Hanmi Pharmaceutical Co Ltd
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Assigned to HANMI PHARM. CO., LTD. reassignment HANMI PHARM. CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHANG, YOUNG-KIL, JUNG, KEUM-SHIN, LEE, GWAN-SUN, LEE, JAE-HEON, PARK, CHUL-HYUN, PARK, GHA-SEUNG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to a method of preparing cefpodoxime proxetil of high purity from cefpodoxime.
  • Cefpodoxime proxetil (R,S)-1-(isopropoxycarbonyloxy)ethyl-(+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-((Z)-methoxyimino)acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate, is a cephalosporin ester pro-drug which, when orally administered, converts to cefpodoxime, an antibacterial agent, through rapid hydrolysis by esterases present on the intestinal wall.
  • Cefpodoxime exhibits a wide range of antibacterial activity against gram positive and negative bacteria, e.g., Staphylococcus aureus, Streptococcus aureus, E. coli, Klebsiella pneumonia and Proteuse vulgaris , and also a high degree of ⁇ -lactamase stability.
  • cefpodoxime proxetil of formula (I) is a ⁇ 3 -isomer prepared by various methods.
  • Hideo Nakao and Koich Huzimoto et al. reported a method of preparing cefpodoxime proxetil by reacting cefpodoxime with iodoalkylcarbonate in the presence of a base such as dicyclohexylamine (see J. of Antibiotics , vol. 40, pp. 370 (1987)). But the product obtained by this method is contaminated by about 3 weight % of the ⁇ 2 -isomers of formula (II) formed as a by-product. Due to the structure similarity, it is very difficult to separate the undesired by-product from the ⁇ 3 -isomer. The conversion of the ⁇ 2 -isomer to the ⁇ 3 -isomer has been attempted, but this process requires a series of reactions, and thus is not economically feasible.
  • U.S. Pat. No. 5,498,787 discloses a method of preparing cefpodoxime proxetil from a cefpodoxime salt using a quaternary ammonium salt phase transfer catalyst, e.g., tetrabutylammonium hydrogensulfate in an amount ranging from 35 to 120 mole % based on cefpodoxime.
  • the method can effectively inhibit the formation of the ⁇ 2 -isomer, but has problems in that the yield of the desired products is very low in the range of 50 to 60%, and the use of expensive quaternary ammonium salts is required.
  • cefpodoxime proxetil is prepared by reacting a cephem compound of cefpodoxime with an alkylcarbonate to obtain an ester and then acylating the ester with an active ester form of arinothiazolyl acetic acid in the presence of a large amount of a quaternary ammonium salt.
  • This method also requires the use of expensive quaternary ammonium salts and suffers from low productivity due to a long process time of about 3 days.
  • cefpodoxime proxetil of formula (I) which comprises reacting a cefpodoxime salt of formula (III) with 1-iodoethylisopropylcarbonate of formula (IV) in an organic solvent in the presence of a crown ether of formula (V):
  • FIGS. 1 to 4 show high performance liquid chromatography (HPLC) scans of cefpodoxime proxetil products obtained by: the method of the present invention (FIG. 1 ); a method without using a crown ether catalyst (FIG. 2 ); and
  • FIG. 5 that of a commercial product.
  • the method of the present invention makes it possible to prepare highly pure cefpodoxime proxetil with only a minimal amount of the ⁇ 2 -isomer, by way of reacting a cefpodoxime salt with 1-iodoethylisopiropylcaibonate using a crown ether as a catalyst.
  • cefpodoximne salt which is used as the sarting material in the present invention may be a cefpodoxime alkali metal or alkaline earth metal salt, and representative examples thereof include cefpodoxime sodium, potassium, calcium and magnesium salts, or a mixture thereof, among which cefpodoxime sodium salt is preferred.
  • 1-iodoethylisopropylcarbonate is employed in an amount ranging from 1 to 3 equivalents, preferably from 1.2 to 1.5 equivalents, based on the amount of the cefpodoxime salt.
  • 1-iodoethylisopropylcarbonate is added to the cefpodoxime salt slowly or in portions, the formation of the A 2 -isomer tends to increase, and thus, the addition of 1-iodoethylisopropylcarbonate is carried out in one shot.
  • the inventive reaction may be performed at a temperature ranging from ⁇ 10 to 40° C., preferably from 0 to 30° C., for a period ranging from 0.5 to 3.0 hours, preferably from 0.5 to 1.5 hours, in an organic solvent such as acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylsulfoxide and N,N-dimethylacetamide, preferably in N,N-dimethylacetamide.
  • an organic solvent such as acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylsulfoxide and N,N-dimethylacetamide, preferably in N,N-dimethylacetamide.
  • Crown ether of formula (V) which is used as a catalyst in the present invention may be referred to as 12-crown-4, 15-crown-5 and 18-crown-6, when m is 4, 5 and 6, respectively.
  • the crown ether catalyst is employed in an amount ranging from 0.5 to 5% by weight based on the weight of the cefpodoxime salt. When the amount of the crown ether catalyst is less than 0.5% by weight, the formation of the ⁇ 2 -isomer increases, while at an amount of more than 5% by weight, the purity of the ⁇ 3 -isomer does not improve significantly. In case the inventive crown ether is not employed, the amount of the ⁇ 2 -isomer formed reaches the range of 6 to 8% by weight.
  • the method of the present invention is very simple and provides highly pure cefpodoxime proxetil which contains less than 0.5% of the ⁇ 2 -isomer.
  • the aqueous layer was extracted with 20 ml of ethyl acetate, the ethyl acetate layers were combined, and washed with a mixture of 30 ml of water and 1 ml of saturated aqueous sodium bicarbonate solution and then with 30 ml of saturated saline.
  • the ethyl acetate solution was treated with activated carbon and anhydrous magnesium sulfate, filtered and concentrated under a reduced pressure to obtain an oily residue.
  • 40 ml of isopropyl ether was added to the residue, stirred for 30 minutes and filtered to obtain 2.13 g of pale yellow cefpodoxime proxetil (yield: 86%).
  • FIG. 1 An HPLC scan of the product is shown in FIG. 1, wherein only a trace amount (0.25%) of the ⁇ 2 -isomer is observed at a retention time of 7.839, while the R- and S-isomers of cefpodoxime proxetil, observed at retention times of 8.338 and 9.350, respectively, constitute 99.0% of the total product.
  • the aqueous layer was extracted with 20 ml of ethyl acetate, the ethyl acetate layers were combined, and washed with a mixture of 30 ml of water and 1 ml of saturated aqueous sodium bicarbonate solution and then with 30 ml of saturated saline.
  • the ethyl acetate solution was treated with activated carbon and anhydrous magnesium sulfate, filtered and concentrated under a reduced pressure to obtain a yellowish red oily residue.
  • 40 ml of isopropyl ether was added to the residue, stirred for 30 minutes, and filtered to obtain 2.02 g of pale yellow cefpodoxime proxetil (yield: 84%).
  • the aqueous layer was extracted with 30 ml of ethyl acetate, the ethyl acetate layers were combined, and washed with a mixture of 60 ml of water and 2 ml of saturated aqueous sodium bicarbonate solution and then with 60 ml of saturated saline.
  • the ethyl acetate solution was treated with activated carbon and anhydrous magnesium sulfate, filtered and concentrated under a reduced pressure to obtain a light reddish brown oily residue.
  • 80 ml of isopropyl ether was added to the residue, stirred for 30 minutes, and filtered to obtain 3.12 g of pale yellow cefpodoxime proxetil (yield: 82%).
  • the aqueous layer was extracted with 30 ml of ethyl acetate, the ethyl acetate layers were combined, and washed with a mixture of 50 nil of water and 4 ml of saturated aqueous sodium bicarbonate solution and then with 50 ml of saturated saline.
  • the ethyl acetate solution was treated with activated carbon and anhydrous magnesium sulfate, filtered and concentrated under a reduced pressure to obtain a yellowish red oily residue.
  • 80 ml of isopropyl ether was added to the residue, stirred for 30 minutes, and filtered to obtain 3.04 g of pale yellow cefpodoxime proxetil (yield: 81%).
  • Example 2 The procedure of Example 1 was repeated except that no crown ether was employed, to obtain 2.08 g of pale yellow cefpodoxime proxetil (yield: 83%).
  • the HPLC scan shown in FIG. 2 suggests that the product contains 7.03% of the ⁇ 2 -isomer (retention time: 7.824) and 91.9% of the ⁇ 3 -isomer (a mixture of the R- and S-isomers at retention times of 8.338 and 9.350, respectively).
  • the HPLC scan shown in FIG. 3 suggests that the product contains 3.0% of the ⁇ 2 -isomer (retention time: 6.907) and 96.8% of the ⁇ 2 -isomer (a mixture of the R- and S-isomers at retention times of 7.369 and 8.292, respectively).
  • cefpodoxime sodium salt 2.0 g was suspended in 11 ml of N,N-dimethylacetamide, and 0.6 g of tetrabutylammonium hydrogensulfate and 1.26 g of 1-iodoethylisopropylcarbonate were added thereto at 20° C. The mixture was kept at room temperature, and samples were taken therefrom at reaction times of 1.5 hours, 3 hours and 7 days to be analyzed by HPLC.
  • the HPLC scan of the sample taken after 7 days is shown in FIG. 4 .
  • An analysis of the result shows the formation of 0.43% of the ⁇ 2 -isomer (retention time: 5.925) together with only 22.6% of the ⁇ 3-isomer (a mixture of R- and S-isomers at retention times of 6.582 and 7.098, respectively).
  • the HPLC scan of a commercial cefpodoxime proxetil sample shown in FIG. 5 suggests that it is composed of 1.44% of the ⁇ 2 -isomer (retention time: 7.840) and 98.1% of the ⁇ 3 -isomer (a mixture of R- and S-isomers at retention times of 8.342 and 9.354, respectively).
  • the method of the present invention is capable of providing highly pure cefpodoxime proxetil in a high yield, as compared with the conventional method.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US10/111,557 1999-11-08 2000-11-07 Method of preparing highly pure cefpodoxime proxetil Expired - Lifetime US6639068B1 (en)

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KR1999-49174 1999-11-08
KR1019990049174A KR100342944B1 (ko) 1999-11-08 1999-11-08 고순도 세프포독심 프록세틸의 제조방법
PCT/KR2000/001272 WO2001034611A1 (en) 1999-11-08 2000-11-07 Method of preparing highly pure cefpodoxime proxetil

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EP (1) EP1228074B1 (es)
JP (1) JP3751880B2 (es)
KR (1) KR100342944B1 (es)
CN (1) CN1160361C (es)
AT (1) ATE297933T1 (es)
AU (1) AU755284B2 (es)
BR (1) BR0015411A (es)
CA (1) CA2389039A1 (es)
DE (1) DE60020869T2 (es)
ES (1) ES2240200T3 (es)
RU (1) RU2217434C1 (es)
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WO (1) WO2001034611A1 (es)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040092734A1 (en) * 2001-02-27 2004-05-13 Yatendra Kumar Cefpodixime proxetil
US20060009639A1 (en) * 2002-11-22 2006-01-12 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of cefpodoxime proxetil
US20060149055A1 (en) * 2003-01-06 2006-07-06 Gharpure Milind M Process for the manufacture of cefpodoxime proxetil
US20060293296A1 (en) * 2002-12-20 2006-12-28 Gharpure Milind M Process for the preparation of cefpodoxime procetil
US20090269400A1 (en) * 2005-05-16 2009-10-29 Elan Pharma International Limited Nanoparticulate and Controlled Release Compositions Comprising a Cephalosporin
WO2010097675A1 (en) 2009-02-27 2010-09-02 Dhanuka Laboratories Ltd. An improved preparation process for cefpodoxime proxetil
EP2520578A1 (en) 2011-05-06 2012-11-07 Lupin Limited Process for purification of cephalosporins

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT408226B (de) * 1999-05-05 2001-09-25 Biochemie Gmbh Kristalliner 7-(2-(2-formylaminothiazol-4-yl)-2
CN1305876C (zh) * 2004-01-08 2007-03-21 上海三维制药有限公司 制备高纯度头孢泊肟酯的方法
CN109232609B (zh) * 2018-09-27 2021-07-02 浙江普洛得邦制药有限公司 一种制备高纯度头孢泊肟酯的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1598568A (en) 1977-04-19 1981-09-23 Glaxo Lab Ltd Esters of(6r,7r)-3-carbamoyloxymethyl-7-((z)-2-(fur-2-yl)-2-methoxyiminoacetamido)-ceph-3-em-4-carboxylic acid
US4486425A (en) * 1980-09-30 1984-12-04 Sankyo Company Limited 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylates
EP0620225A1 (en) 1993-04-16 1994-10-19 F. Hoffmann-La Roche Ag Cephalosporin derivatives
US5498787A (en) * 1994-04-20 1996-03-12 Standard Chemical & Pharmaceutical Co., Ltd. Method for preparing cephalosporin derivatives
US5789585A (en) * 1995-06-19 1998-08-04 Brookhaven Science Associates Llc Aza crown ether compounds as anion receptors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1598568A (en) 1977-04-19 1981-09-23 Glaxo Lab Ltd Esters of(6r,7r)-3-carbamoyloxymethyl-7-((z)-2-(fur-2-yl)-2-methoxyiminoacetamido)-ceph-3-em-4-carboxylic acid
US4486425A (en) * 1980-09-30 1984-12-04 Sankyo Company Limited 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylates
EP0620225A1 (en) 1993-04-16 1994-10-19 F. Hoffmann-La Roche Ag Cephalosporin derivatives
US5498787A (en) * 1994-04-20 1996-03-12 Standard Chemical & Pharmaceutical Co., Ltd. Method for preparing cephalosporin derivatives
US5789585A (en) * 1995-06-19 1998-08-04 Brookhaven Science Associates Llc Aza crown ether compounds as anion receptors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
The Journal of Antibiotics, vol. 40, Mar. 1987, 370-384 , Koichi Fujimoto, et al.

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040092734A1 (en) * 2001-02-27 2004-05-13 Yatendra Kumar Cefpodixime proxetil
US7045618B2 (en) * 2001-02-27 2006-05-16 Ranbaxy Laboratories Limited Cefpodixime proxetil
US20060009639A1 (en) * 2002-11-22 2006-01-12 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of cefpodoxime proxetil
US20060293296A1 (en) * 2002-12-20 2006-12-28 Gharpure Milind M Process for the preparation of cefpodoxime procetil
US20060149055A1 (en) * 2003-01-06 2006-07-06 Gharpure Milind M Process for the manufacture of cefpodoxime proxetil
US20090269400A1 (en) * 2005-05-16 2009-10-29 Elan Pharma International Limited Nanoparticulate and Controlled Release Compositions Comprising a Cephalosporin
WO2010097675A1 (en) 2009-02-27 2010-09-02 Dhanuka Laboratories Ltd. An improved preparation process for cefpodoxime proxetil
EP2520578A1 (en) 2011-05-06 2012-11-07 Lupin Limited Process for purification of cephalosporins

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EP1228074A1 (en) 2002-08-07
JP3751880B2 (ja) 2006-03-01
EP1228074B1 (en) 2005-06-15
ES2240200T3 (es) 2005-10-16
CN1160361C (zh) 2004-08-04
EP1228074A4 (en) 2003-02-26
AU1420201A (en) 2001-06-06
JP2003513983A (ja) 2003-04-15
TR200201243T2 (tr) 2002-09-23
CA2389039A1 (en) 2001-05-17
WO2001034611A1 (en) 2001-05-17
BR0015411A (pt) 2002-06-25
KR20010045748A (ko) 2001-06-05
ATE297933T1 (de) 2005-07-15
DE60020869T2 (de) 2005-11-03
KR100342944B1 (ko) 2002-07-02
AU755284B2 (en) 2002-12-05
RU2217434C1 (ru) 2003-11-27
DE60020869D1 (de) 2005-07-21
CN1387533A (zh) 2002-12-25

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